a pilot preoperative trial of ganetespib with paclitaxel for triple-negative breast cancer

Conditions: Breast Cancer

Summary: based on preclinical data implicating gr, ar, and jak/stat activation as potent mechanisms of breast cancer cell survival despite chemotherapy administration (i.e. chemotherapy resistance), the study will test a novel approach for improving chemotherapy effectiveness by adding hsp90 inhibition to antagonize the anti-apoptotic signaling pathways that are initiated via gr, ar, and jak/stat activation.

study objectives primary: • to determine tumor gr, ar, jak and other hsp90 client protein expression before and after two weeks of ganetespib monotherapy secondary: * to determine the pathological complete response (pcr) rate associated with weekly treatment of ganetespib plus paclitaxel followed by the combination treatment of doxorubicin plus cyclophosphamide * to characterize the toxicity of study treatment

Eligibility criteria:
inclusion criteria: * invasive carcinoma of the breast * er negative and pr negative tumors defined as \< 1% of tumor nuclei that are immunoreactive for er and pr * her2 non-overexpressing status documented as: * fish ratio of less than 2.0, or * ihc staining of 0 or 1+ * no evidence of distant metastatic disease. patients with regional lymph node involvement are eligible. * \>18 years old * female * no prior treatment for the disease under study * no prior treatment within 5 years for any other cancer including chemotherapy, surgery (except for diagnostic biopsy), radiotherapy, hormonal therapy, or investigational agents, unless curative treatment of non-melanoma skin-cancer or in-situ cancer * able to understand and sign an informed consent (or have a legal representative who is able to do so) * clinically or radiologically measureable disease in the breast after diagnostic biopsy, defined as longest diameter greater than or equal to 2cm * willing to undergo three mandatory core biopsies after diagnosis to obtain tissue for biologic expression profiling. * an eastern cooperative oncology group (ecog) performance status (ps) of 0 or 1 * adequate bone marrow reserves as evidenced by: * leukocytes \> 3,000/μl * absolute neutrophil count (anc) \> 1,500/μl without the use of hematopoietic growth factors, * platelet count \> 100,000/μl, and * hemoglobin \> 9 g/dl * adequate hepatic function as evidenced by: * serum total bilirubin within institutional normal limits * aspartate aminotransferase (ast), alanine aminotransferase (alt) and alkaline phosphatase less than or equal to 2.5 × uln * adequate renal function as evidenced by a serum creatinine within uln or creatinine clearance \> 60 ml/min/1.73 m2 for patients with creatinine levels above institutional normal * eligible for treatment with paclitaxel, doxorubicin and cyclophosphamide * if of childbearing potential, are willing to abstain from sexual intercourse or to use an effective form of contraception (e.g., a double-barrier method) during the study and for 90 days following the last dose of ganetespib exclusion criteria: * • patients may not be receiving any other investigational agents. * patients may not have a known hypersensitivity to any of the components of ganetespib * patients may not have a history of severe allergic reactions to paclitaxel or other drugs formulated in cremaphor® el. * patients with a qtc \> 470 ms, a family history of long qt syndrome, and those on medications known to cause torsades de pointes will be excluded from the study. * patients may not have an uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * patients may not have new york heart association (nyha) class iii or iv congestive heart failure or left ventricular ejection fraction (lvef) \< 50%. * as patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy, hiv-positive patients receiving combination anti-retroviral therapy are excluded from the study. * patients may not have a need for chronic systemic steroid therapy * patients may not be pregnant or breastfeeding

Keywords: triple-negative breast cancer